Ro 48-8.071, a new 2,3-oxidosqualene:lanosterol cyclase inhibitor lowering plasma cholesterol in hamsters, squirrel monkeys, and minipigs: comparison to simvastatin.

Himber J.

F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Basel, Switzerland.

2,3-Oxidosqualene:lanosterol cyclase (OSC, E.C. 5.4.99.7) represents a unique target for a cholesterol lowering drug. Partial inhibition of OSC should reduce synthesis of lanosterol and subsequent sterols, and also stimulate the production of epoxysterols that repress HMG-CoA reductase expression, generating a synergistic, self-limited negative regulatory loop. Hence, the pharmacological properties of Ro 48-8.071, a new OSC inhibitor, were compared to that of an HMG-CoA reductase inhibitor, simvastatin. Ro 48-8.071 blocked human liver OSC and cholesterol synthesis in HepG2 cells in the nanomolar range; in cells it triggered the production of monooxidosqualene, dioxidosqualene, and epoxycholesterol. It was safe in hamsters, squirrel monkeys and Gottingen minipigs at pharmacologically active doses, lowering LDL approximately 60% in hamsters, and at least 30% in the two other species, being at least as efficacious as safe doses of simvastatin. The latter was hepatotoxic in hamsters at doses > 30 mumol/kg/day limiting its window of efficacy. Hepatic monooxidosqualene increased dose-dependently after treatment with Ro 48-8.071, up to approximately 20 micrograms/g wet liver or less than 1% of hepatic cholesterol, and it was inversely correlated with LDL levels. Ro 48-8.071 did not reduce coenzyme Q10 levels in liver and heart of hamsters, and importantly did not trigger an overexpression of hepatic HMG-CoA reductase, squalene synthase, and OSC itself. In strong contrast, simvastatin stimulated these enzymes dramatically, and reduced coenzyme Q10 levels in liver and heart. Altogether these findings clearly differentiate the OSC inhibitor Ro 48-8.071 from simvastatin, and support the view that OSC is a distinct key component in the regulation of the cholesterol synthesis pathway.

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The effect of Simvastatin on the plasma antioxidant concentrations in patients with hypercholesterolaemia.

Potgieter HC.

Department of Chemical Pathology, University of Pretoria, South Africa.

The aim of this study was to monitor the antioxidant status of patients with hypercholesterolaemia during treatment with Simvastatin. Forty-seven patients, of whom 25 had confirmed familial hypercholesterolaemia (FH), were treated with 10 or 20 mg of Simvastatin per day for 14 weeks. As expected, total cholesterol and LDL cholesterol concentrations decreased considerably, while HDL cholesterol concentrations increased during drug treatment. In neither FH nor non-FH patients were any significant changes observed for retinol status, while plasma vitamin C concentrations were also not adversely affected by the drug therapy. In both patient groups Simvastatin therapy led to a significant decrease in plasma alpha-tocopherol (P < 0.05) concentrations, however, the alpha-tocopherol/total cholesterol ratio increased by 9.1 (P < 0.01) and 12.1% (P < 0.01) in FH and non-FH patients, respectively, during the 14-week treatment period. The coenzyme Q10/total cholesterol ratio did not change significantly in non-FH patients, but was significantly lower (P < 0.05) than the baseline ratio after 4 and 14 weeks of Simvastatin treatment in FH patients. The alpha-tocopherol/total cholesterol ratio of FH patients remained consistently and significantly lower (P < 0.01) compared with non-FH patients, indicating that LDL from the former group may be more vulnerable to free radical-mediated damage and lipid peroxidation. Our results suggest that the significant decline in circulating alpha-tocopherol and coenzyme Q10 concentrations was mainly a function of the decrease in serum total cholesterol concentrations.

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Rosuvastatin: new preparation. Opt for statins with evidence of efficacy on clinical outcome.

.

(1) Simvastatin and pravastatin are the two reference statins for type IIA and type IIB hypercholesterolaemia because they have the best-documented protective effect against cardiovascular events. Simvastatin and pravastatin are also the reference statins for familial heterozygous hypercholesterolaemia, though there is no evidence that they prevent cardiovascular events in this group. Statins are not very effective in familial homozygous hypercholesterolaemia. (2) Rosuvastatin is the sixth statin to arrive on the French market. The fifth, cerivastatin, was withdrawn from the market in 2001 because of serious adverse effects. (3) Rosuvastatin has not been assessed in terms of morbidity or mortality. The results of comparative trials in type IIA and type IIB hypercholesterolaemia suggest that rosuvastatin is slightly more active than simvastatin, pravastatin and atorvastatin on some lipid parameters after a few weeks of treatment. (4) Rosuvastatin has not been compared with simvastatin or pravastatin in familial heterozygous hypercholesterolaemia. One trial showed it to be slightly more effective than atorvastatin on cholesterol levels. According to one trial, rosuvastatin does not appear to be more effective than atorvastatin in homozygous forms. (5) In clinical trials the adverse effects of rosuvastatin were similar to those of other statins, with the exception of renal adverse effects. We don't know whether rosuvastatin is more or less likely than other statins to cause rhabdomyolysis. (6) Clinical trials reported some cases of proteinuria and renal failure suggesting there is a need for more thorough assessment in long-term trials. (7) In practice, statins with the best-documented benefits (simvastatin and pravastatin) should be used first for cardiovascular prevention in patients with hypercholesterolaemia.

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Effects of simvastatin on the metabolism of polyunsaturated fatty acids and on glycerolipid, cholesterol, and de novo lipid synthesis in THP-1 cells.

Galli C.

Institute of Pharmacological Sciences, University of Milan, Milano, Italy.

In the monocytic THP-1 cells, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor simvastatin (5 microM) enhances the conversion of exogenous linoleic (18:2 n-6) and eicosapentaenoic (20:5 n-3) acids to their long-chain polyunsaturated fatty acid (LC-PUFA) derivatives, and this effect is associated with changes in the desaturation steps. In addition, formation of monounsaturated fatty acids from endogenously synthesized precursors is increased. These metabolic changes lead to elevated LC-PUFA and fatty acid (FA) unsaturation in cells. The effects of simvastatin on FA metabolism are associated with increased synthesis of triglycerides from glycerol. The dose-effect relationships for the activity of simvastatin on total linoleic acid (LA) conversion and cholesterol synthesis reveal that enhancement of PUFA metabolism is already maximal at 0.5 microM simvastatin, whereas cholesterol synthesis is further inhibited by concentrations of simvastatin up to 5 microM. The effects of 5 microM simvastatin on PUFA metabolism are partially prevented by mevalonate (1 mM) and geranylgeraniol (5 microM) but not by farnesol (10 microM). These data indicate that HMG-CoA inhibitors have profound effects on PUFA metabolism, and that the pathways for cholesterol and PUFA synthesis are mutually modulated.

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Effects of ketoconazole on plasma lipids and lipoprotein(a) in familial hypercholesterolaemia, compared with simvastatin.

de Graaf J.

Department of Medicine, University Hospital Nijmegen, The Netherlands. A.Stalenhoef aig.azn.nl

BACKGROUND: Ketoconazole is an imidazole derivative that is active as a broad-spectrum antifungal agent. It is also an inhibitor of cholesterol production both in vivo and in vitro. METHODS: We compared the effect of low-dose ketoconazole (200 mg/day) or simvastatin (20-40 mg/day) on lipids, lipoproteins and lipoprotein(a) [Lp(a)] in 10 patients with familial hypercholesterolaemia. RESULTS: Ketoconazole reduced serum total cholesterol and low-density lipoprotein (LDL)-cholesterol by 7.6 and 9.7%, respectively. Simvastatin was more effective, the respective changes being -34.4 and -40.6%. Serum triglycerides and high-density lipoprotein (HDL) were unchanged by ketoconazole therapy, whereas simvastatin decreased triglyceride levels by 33.8% and increased HDL-cholesterol levels by 8.7%. Median Lp(a) levels tended to increase during simvastatin and to decrease during ketoconazole therapy. However, due to the wide range of baseline concentrations of Lp(a), these changes were not significant. CONCLUSIONS: Ketoconazole has some hypocholesterolaemic potential, but the effect of simvastatin is much more pronounced. The increase in Lp(a) during simvastatin therapy has been reported earlier, whereas ketoconazole does not exhibit an effect on the level of Lp(a).

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[Data on cholesterol level screening of patients with ischemic heart disease in the light of the Scandinavian Simvastatin Survival Study]

[Article in Hungarian]

Simondan G.

Bekes Megyei Kepviselotestulet Pandy Kalman Korhaza, II. Belgyogyaszat-Kardiologia Gyula.

The authors carried out a coronary heart disease risk factor screening on 1240 people of two villages of Bekes county, Hungary. The prevalence of coronary heart disease among the 969 people 35-70 years old was 12.0%, in the different age groups varied between 0.8 and 20.9%. This high prevalence could be explained by the high occurence of the different risk factors. The results of cholesterol levels were analysed according to that of Scandinavian Simvastatin Survival Study. From 35-70 years old screened people with coronary heart disease 77 had a cholesterol level between 5.5 and 8.0 mmol/l. In these patients with 20-40 mg daily dose of simvastatin during 5.4 years long treatment from 7 predicted coronary death 3, from 17 expected non fatal myocardial infarction 5, from 13 anticipated revascularisation procedures 5 would be preventable. The 5.4 years long treatment with 20 mg simvastatin calculated with the prices of July 1996 in Hungary would cost 292831 forints, from which 87847 has to be paid by the patient. If the decrease of hospitalization costs of the coronary heart disease patients treated with simvastatin is also taken into account, the drug treatment costs, according to the literature, could be reduced with additional 88%.

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